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Schiller, Christian B.; Braciak, Todd A.; Fenn, Nadja C.; Seidel, Ursula J. E.; Roskopf, Claudia C.; Wildenhain, Sarah; Honegger, Annemarie; Schubert, Ingo A.; Schele, Alexandra; Lämmermann, Kerstin; Fey, Georg H.; Jacob, Uwe; Lang, Peter; Hopfner, Karl-Peter; Oduncu, Fuat S. (2016): CD19-specific triplebody SPM-1 engages NK and gd T cells for rapid and efficient lysis of malignant B-lymphoid cells. In: Oncotarget, Vol. 7, No. 50: pp. 83392-83408
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Abstract

Triplebodies are antibody-derived recombinant proteins carrying 3 antigen-binding domains in a single polypeptide chain. Triplebody SPM-1 was designed for lysis of CD19-bearing malignant B-lymphoid cells through the engagement of CD16-expressing cytolytic effectors, including NK and gd T cells. SPM-1 is an optimized version of triplebody ds(19-16-19) and includes humanization, disulfide stabilization and the removal of potentially immunogenic sequences. A three-step chromatographic procedure yielded 1.7 - 5.5 mg of purified, monomeric protein per liter of culture medium. In cytolysis assays with NK cell effectors, SPM-1 mediated potent lysis of cancer-derived B cell lines and primary cells from patients with various B-lymphoid malignancies, which surpassed the ADCC activity of the therapeutic antibody Rituximab. EC50-values ranged from 3 to 86 pM. Finally, in an impedance-based assay, SPM-1 mediated a particularly rapid lysis of CD19-bearing target cells by engaging and activating both primary and expanded human gd T cells from healthy donors as effectors. These data establish SPM-1 as a useful tool for a kinetic analysis of the cytolytic reactions mediated by gd T and NK cells and as an agent deserving further development towards clinical use for the treatment of B-lymphoid malignancies.